17-thioandrostadienes



Patented June 3, 1958 Pic 2,837,538 unnoxnnnosrwmuns Raymond M. Dodson, Park Ridge, and Paul B. Sollman, Skokie, 11]., assignors to G. D. Searle & Co Chicago,

11]., a corporation of Delaware No Drawing. Application April 19, B56 Serial No. 579,135

9 Claims. (Cl, 260-397.?!)

BR CHa wherein R is a lower alkyl or a lower alkanoyl radical, and the 5,16-androstadiene derivatives of the structural formula wherein R is defined as hereinbefore and R is hydrogen or a lower alkanoyl radical.

Among the lower alkyl radicals which the term R can represent are methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl and branched-chain isomers thereof. The expression lower alkanoyl is defined herein to mean an acyl radical of an alkanoic acid containing fewer than 9 carbon atoms. The lower alkanoyl radicals embraced in this definition consequently include formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl and branched-chain isomers thereof.

The compounds of this invention can be prepared from such starting materials as 3B-hydroxy-5-androstene-l7- thione, described in our copending application, Serial No. 485,606, filed February 1, 1955, now U. S. Patent No. 2,753,361, and 3-oxo-4-androstene-l7-thione, described in our copending application, Serial No. 491,507, filed March 1, 1955, now U. S. Patent No. 2,763,669. For convenience in visualizing the processes of the present invention,

the products described and claimed herein can be regarded as derived from the enethiol forms of the thioketones named as starting materials. ,It will be apprecated, however, that while these enethiols are useful in the formulation of concepts of the described reactions, the free euethiols themselves are believed to be incapable of 2 stable existence independent of the thioketones to which they are related.

Treatment of a steroidal l'7-thioketone of the types named hereinbefore with an alkylating reagent such as a dialkyl sulfate in abasic medium, or a mixture comprising a lower alkanol, an alkali metal alkoxide and an alkyl halide results in the formation of an alkylation product which is structurally related to the enethiol form of the parent thioketone. Thus, l7-methylthio-5,l6-androstadien-3B-ol is obtained by the treatment of 3fi-hydroxy- 5-androstene-l7-thione in methanolic solution with sodium methoxide and methyl iodide.

Acyl derivatives are obtained by treatment of the parent thioketone with an acylating medium comprising a basic catalyst such as pyridine and a lower alkanoic acid anhydride, or a lower alkanoyl halide. Thus, treatment of 3-oxo-4-androstene-17-thione with a mixture of pyridine and acetic anhydride yields l7-acetylthio-4,l6-androstadien-3-one, and treatment of 3li-hydroxy-5-androstene-17- thione with pyridine and acetic anhydride yields the diacetyl derivative, 3fi-acetoxy-l7-acetylthio-5,l6-androstadiene..

Other alkylation and acylation products, homologously related to those described hereinbefore, are obtained by suitable selection of the alkylating or acylating reagent, 'as illustrated in the examples to follow.

A noteworthy feature of this invention is that the alkyl and alkanoyl derivatives related to the enethiol structure are formed with an ease which is totally unpredictable from a consideration of the chemical behavior of the oxygen analogs of the parent l7-thioketones. Thus, while formation of enolic derivatives of a steroidal 17-ketone proceeds under relatively drastic conditions or not at all, the enethiolic compounds of this invention are formed in high yields and in excellent states of purity under un-l expectedly mild conditions.

The compounds of this invention have useful pharmacological actions, including hormonal and anti-hormonal properties not substantially analogous to those of their 16,17-dihydro derivatives. They are anti-inflammatory agents, as shown by their effectiveness in reducing inflammation of the iris. The compounds of this inven- 7 tion are also effective in decreasing the serum ratio of cholesterol to phospholipids, and they produce this change, useful in the treatment of hyperchloesterolemia and disorders associated therewith Without producing the excessive estrogenic side-effects commonly associated with therapeutic agents which regulate cholesterol transport and metabolism.

The compounds of this invention are also useful as intermediates. in organic syntheses. For example, by oxidation with a peroxy acid such as perbenzoic acid, they yield sulfoxides and sulfones. As a specific example, oxidation of 17-me'thylthio-4,16-androstadien-3-one with 2 molecular equivalents of perbenzoic acid yields 17- methylsulfonyl-4,l6-androstadien-3-one. This compound has anti-infective and, in particular, anti-viral properties. When administered with cortisone, it inhibits the ability of cortisone to promote a Coxsackie virus infection.

This invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade (C.) and quantities of materials in parts by Weight.

Example 1 A solution prepared from 8 parts of. 3p-hydroxy-5-- sodium methoxide and 3.8 parts of methyl iodide is allowed to stand for 3 hours at room temperature. The product obtained by diluting the mixture with water is collected on a filter. By recrystallization from aqueous methanol there is obtained 17-methylthio-5,l6-nndrostadien-flfi-ol melting at about 165166 C. This compound has the structural formula SCH: H;

and 1.23 parts of l-iodobutane is allowed to stand at room temperature for 16 hours- It is then concentrated under reduced pressure, suitably at a temperature of.

less than 50 C., to about of its original volume, and diluted with about 150 parts of water. The insoluble product is collected, washed and recrystallized from methanol or aqueous methanol, whereby there is obtained l7-butylthio-5,l6-androstadien-3fl-ol of the structural formula SC4H0 Example 3 A solution is prepared from 9 parts of 3B-hydroxy-5- androstene-l7-thione, 80 parts of methanol, 1.6 parts of sodium methoxide and 6.2 parts of l-iodopropane. An

insoluble reaction product soon appears, and when its separation is complete, it is collected on a filter and washed. This compound is l7-propylthio-5,l6-androstadien-3g3-ol which melts at about l35-l38 C. and has the structural formula SCHQOHQCH! CH;

Example 4 A mixture of 1 part of l7-methylthio-5,l6-androstadien- 35-01, 10 parts of pyridine and 2.5 parts of butyric anhydride is allowed to stand for 18 hours at about 25 C. The reaction mixture is diluted with several times its volume of water, and when separation of the insoluble reaction product is complete, it is'collected and washed. This compound is 3fi-butyroxy-l7-methylthio-5,16-androstadiene (l7-rnethylthio-5,l6-androstadien3B-ol butyrate).

Example 5 A solution of 65 parts of 3/3-hydroxy-5-androstene-17- thione, 500 parts of pyridine and 540 parts of acetic anhydride is allowed to stand for 18 hours at about C. The reaction mixture is poured into several times its volume of ice water and allowed to stand until separation of the insoluble product is complete. This crude product is collected on a filter, washed with water and dried. Purification by repeated crystallizations from pe troleum ether yields the diacetyl derivative, 3fi-acetoxyl7-acetylthio-5,16-androstadiene melting at about 139 141 C. This compound has the structural formula SCOCH: CH5

CHaCOO Example 6 i A solution of 1 part of 3fi-hydroxy-5-androstene-l7- thione, 10 parts of pyridine and 5 parts of propionic.

anhydride is allowed to stand for 24 hours at about 25 C. The reaction mixture is diluted with several times its volume of ice Water, and the insoluble product is collected and washed with water. This compound is the dipropionyl derivative, 3B-propionoxy-l7-propionylthio-5, l6-androstadiene.

Example 7 i A solution of aluminum isopropoxide is prepared by stirring 12 parts of this compound with 45 parts of toluene, and by decanting from the small amount of insolu ble residue. This solution of aluminum isopropox'ide is mixed with 11.1 parts of 17 methylthio 5,16 androsj tadien-SB-ol, 76 parts of cyclohexanone and 440' parts of toluene, and this reaction mixture is heated under reflux for minutes. of 50 parts of sodium potassium tartrate in 200 parts of water, and the resulting mixture is distilled with steam l7-methylthio-4,l6-androstadien-3-one melting at -about 188-190 C. This compound has the structural formula.

SCH:

The same compound is obtained by allcylation of 3-oxo- 4-androstene-l7-thione with methyl iodide by the procedure of Example 1.

Example 8 tion of aluminum isopropoxide, 6 parts of l7-butylthio 5,l6-androstadien-3fl-ol, parts of cyclohexanone and 260 parts of toluene is heated under reflux for 30 min- There is then added a solution Example 9 A solution of 8 parts of 3-oxo4-androstene-17-thione, 50 parts of pyridine and 50 parts of acetic anhydride is allowed to stand for 16 hours at about 25 C. after which it is poured into several times its volume of ice water in order to hydrolyze unreacted acetic anhydride and precipitate the reaction product. When separation of the reaction product is complete, it is collected and su'bjected to a preliminary purification by reprecipitating it from methanol solution by the addition of water. By crystallization of the reprecipitated product from petroether and then from aqueous methanol, there is obtained l7-acetylthio 4,16 androstadien-3-one which melts at about 114-115 C. and has the structural formula.

SC 0 CH: CH;

By the substitution of 30 parts of butyric anhydride for the acetic anhydride in the foregoing procedure, there is obtained 17-butyrylthio-4,16-androstadien-3-one.

Example To a solution of 9.5 parts of l7-methylthio-4,l6-androstadien-S-one in 660 parts of benzene there is added, with stirring, a 0.13 molar solution of perbenzoic acid in benzene containing a total of 8.3 parts of perbenzoic acid. About 30 minutes after all of the perbenzoic acid solution has been added, the mixture is washed with dilute sodium hydroxide solution and with several portions of water, and the organic solution is concentrated to dryness under reduced pressure. Purification by successive crystallizations of the residue from aqueous methanol and from a mixture of ethyl acetate and petroleum ether yields 17- methylsulfonyll,16-androstadien-3-one melting at about 157 C. This compound has the structural formula o= =0 on,

What is claimedis: l. A member of the group of the structural formula consisting of compounds and compounds of the structural formula wherein R is a member of the group consisting of lower alkyl and lower alkanoyl radicals and R is a member of the group consisting of hydrogen and lower alkanoyl radicals.

2. A compound of the structural formula S-(lower alkyl) 3. 17-methylthio-4,16-androstadien-3-one. 4. A compound of the structural formula wherein A is a lower alkanoyl radical.

5. 17-acetylthio-4,16-androstadien-3-one. 6. A compound of the structural formula S-(lower alkyl) 7. 17-methylthio-5,16-androstadien-3fl-ol.

wherein A and A are lower alkauoyl radicals.

9-. 3aetoxy-fl-acetylthio-i16-androstadiene.

Rfereuces Cited in the file of this patent UNITED STATES PATENTS Levin May 1, 1951 Wettstein May 27, 1952 Wettstein May 27, 1952 Rosenkranz Sept. 2, 1952 Rosenkr'auz Dec. 14, 1954 Dodson et al. July 3, 1956 Dodson et a1. Sept. 18, 1956 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,837,538 June 3, 1958 Raymond M, Dodson et al,

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 5 line 31, for "petro read petroleum Signed and sealed this 21st day of October 1958,

SEAL Attest:

KARL H. AXLINE ROBERT C. WATSON Attestina Oflicer Commissioner of Patents 

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE STRUCTURAL FORMULA 